Only a small percentage of marijuana treatment seekers are able to achieve abstinence. This proposal will investigate the interaction between marijuana and potential treatment medications, with the direct goal of using this information to improve marijuana treatment outcome. Our model for marijuana medication development is guided by the hypothesis that attenuating marijuana's positive or negative reinforcing effects will decrease relapse. AIM #1: To determine if the opioid antagonist, naltrexone, decreases marijuana's direct effects, and thus decreases the likelihood that marijuana smokers will relapse to marijuana use; relapse is defined as marijuana self-administration after a period of abstinence. Hypotheses: Naltrexone will decrease marijuana relapse by decreasing its direct effects. AIM #2: To determine if the alpha2-noradrenergic agonist, Iofexidine decreases marijuana withdrawal and thereby decreases relapse. Lofexidine will be compared to oral THC, which decreases marijuana withdrawal symptoms at doses that produce minimal intoxication. Thus, the effects of Iofexidine and oral THC alone and in combination will be determined. Hypotheses: 1) Lofexidine and oral THC alone will decrease a distinct subset of marijuana withdrawal symptoms, and will decrease marijuana relapse; 2) Lofexidine combined with oral THC will result in the largest decrease in marijuana withdrawal symptoms and relapse. AIM #3: To compare the effects of oral THC to THC administered using a newly developed oro-mucosal spray on marijuana withdrawal and relapse. Hypotheses: 1) Spray and oral THC alone will decrease marijuana withdrawal symptoms and relapse; 2) Spray THC will more consistently decrease marijuana withdrawal symptoms and relapse across individuals than oral THC. AIM #4: To determine if the GABAB agonist, baclofen decreases marijuana's direct effects and marijuana withdrawal, and thereby decreases relapse. Hypotheses: Baclofen will decrease marijuana relapse by decreasing both marijuana's direct effects and marijuana withdrawal. There are clear interactions between cannabinoid, opioid and GABA receptors in the CNS, yet the nature of these interactions remains unknown. The strength of this proposal lies in our utilization of a controlled laboratory setting to examine the interactive effects of potential treatment medications on marijuana's direct effects, marijuana withdrawal, and on marijuana relapse.